Proceedings of the annual meeting of the European Consortium of Lipodystrophies (ECLip), Pisa, Italy, 28-29 September 2023.

Lipodystrophy syndromes are rare diseases primarily affecting the development or maintenance of the adipose tissue but are also distressing indirectly multiple organs and tissues, often leading to reduced life expectancy and quality of life. Lipodystrophy syndromes are multifaceted disorders caused by genetic mutations or autoimmunity in the vast majority of cases. While many subtypes are now recognized and classified, the disease remains remarkably underdiagnosed. The European Consortium of Lipodystrophies (ECLip) was founded in 2014 as a non-profit network of European centers of excellence working in the field of lipodystrophies aiming at promoting international collaborations to increase basic scientific understanding and clinical management of these syndromes. The network has developed a European Patient Registry as a collaborative research platform for consortium members. ECLip and ECLip registry activities involve patient advocacy groups to increase public awareness and to seek advice on research activities relevant from the patients perspective. The annual ECLip congress provides updates on the research results of various network groups members.

Clinical Characteristics of Patients With Acquired Partial Lipodystrophy: A Multicenter Retrospective Study.

BACKGROUND: Barraquer-Simons syndrome (BSS) is a rare, acquired form of lipodystrophy characterized by progressive loss of upper body subcutaneous fat, which affects face, upper limbs, and trunk. The pathogenesis of the disease is not entirely known and may involve autoimmune mechanisms. AIM: This study aimed to provide a comprehensive picture of the clinical, immunological, and metabolic features of a large cohort of patients with BSS. Our primary objectives included the validation of existing diagnostic tools, the evaluation of novel diagnostic approaches, and the exploration of potential disease triggers or genetic predispositions. SUBJECTS AND METHODS: Twenty-six patients were diagnosed with BSS based on accepted criteria defined by international guidelines. Anthropometric parameters, biochemical tests, organ- and non-organ-specific autoantibodies, HLA status, and screening of the LMNB2 gene were performed. RESULTS: Patients were predominantly females (73%); fat loss occurred mostly during childhood (77%) at a median age of 8 years. Among various anthropometric measures, the ratio between the proportion of fat mass in upper limbs and lower limbs showed the best predictive value for diagnosis. A total of 11.5% of patients had diabetes, 34.6% dyslipidemia, and 26.9% hepatic steatosis. Seventy-five percent of children and 50% of adults had C3 hypocomplementemia; 76% of patients were positive for 1 or more autoantibodies. HLA-DRB1 11:03 had higher allelic frequencies compared with the general population. A single variant in the LMNB2 gene was found in 1 patient. CONCLUSION: BSS has a childhood onset and is often associated with autoimmune diseases. Skinfold thickness measurements and fat assessment by dual energy X-ray absorptiometry are useful tools to identify the disease. C3 hypocomplementemia and the presence of autoantibodies may be used as additional diagnostic supportive criteria but the prevalence of C3 hypocomplementemia may be lower than previously reported.

SARS-CoV-2 spread to endocrine organs is associated with obesity: an autopsy study of COVID-19 cases.

PURPOSE: SARS-CoV-2 infection may be limited to the respiratory tract or may spread to multiple organs. Besides disease severity, factors associated with virus spread within the host are elusive. Here, we tried to identify features associated with SARS-CoV-2 spread to endocrine organs. METHODS: In a retrospective autoptic cohort of 51 subjects who died because of COVID-19, we analyzed the severity and type of lung pathology, patients' features and the detection of virus in thyroid, testis, adrenal gland, pancreas, anterior pituitary, and the white adipose tissue (WAT). RESULTS: The SARS-CoV-2 genome was detected in endocrine organs of 30/51 cases. The anterior pituitary and WAT were most frequently positive for virus. While pathological features of lung were not associated with the presence of virus in endocrine organs, obesity (BMI > 30) was significantly associated to virus detection in pancreas (p = 0.01) and thyroid (p = 0.04). WAT infection was detected more frequently in males (p = 0.03). CONCLUSION: In subject with obesity dying of COVID-19, the virus frequently spreads to endocrine organs. The findings emphasize the need for optimal treatment of patients with obesity at the very onset of COVID-19. Since post-COVID conditions remain a major issue worldwide, a rigorous follow-up of endocrine function-especially of thyroid and pancreas-is advocated in subjects with obesity.

Vitamin D status and supplementation before and after Bariatric Surgery: Recommendations based on a systematic review and meta-analysis.

Bariatric surgery is associated with a postoperative reduction of 25(OH) vitamin D levels (25(OH)D) and with skeletal complications. Currently, guidelines for 25(OH)D assessment and vitamin D supplementation in bariatric patients, pre- and post-surgery, are still lacking. The aim of this work is to analyse systematically the published experience on 25(OH)D status and vitamin D supplementation, pre- and post-surgery, and to propose, on this basis, recommendations for management. Preoperatively, 18 studies including 2,869 patients were evaluated. Prevalence of vitamin D insufficiency as defined by 25(OH)D < 30 ng/mL (75 nmol/L) was 85%, whereas when defined by 25(OH)D < 20 ng/mL (50 nmol/L) was 57%. The median preoperative 25(OH)D level was 19.75 ng/mL. After surgery, 39 studies including 5,296 patients were analysed and among those undergoing either malabsorptive or restrictive procedures, a lower rate of vitamin D insufficiency and higher 25(OH)D levels postoperatively were observed in patients treated with high-dose oral vitamin D supplementation, defined as ≥ 2,000 IU/daily (mostly D3-formulation), compared with low-doses (< 2,000 IU/daily). Our recommendations based on this systematic review and meta-analysis should help clinical practice in the assessment and management of vitamin D status before and after bariatric surgery. Assessment of vitamin D should be performed pre- and postoperatively in all patients undergoing bariatric surgery. Regardless of the type of procedure, high-dose supplementation is recommended in patients after bariatric surgery.

A new mutation in the CAVIN1/PTRF gene in two siblings with congenital generalized lipodystrophy type 4: case reports and review of the literature.

Lipodystrophy syndromes are characterized by a progressive metabolic impairment secondary to adipose tissue dysfunction and may have a genetic background. Congenital generalized lipodystrophy type 4 (CGL4) is an extremely rare subtype, caused by mutations in the polymerase I and transcript release factor (PTRF) gene. It encodes for a cytoplasmatic protein called caveolae-associated protein 1 (Cavin-1), which, together with caveolin 1, is responsible for the biogenesis of caveolae, being a master regulator of adipose tissue expandability. Cavin-1 is expressed in several tissues, including muscles, thus resulting, when dysfunctional, in a clinical phenotype characterized by the absence of adipose tissue and muscular dystrophy. We herein describe the clinical phenotypes of two siblings in their early childhood, with a phenotype characterized by a generalized reduction of subcutaneous fat, muscular hypertrophy, distinct facial features, myopathy, and atlantoaxial instability. One of the siblings developed paroxysmal supraventricular tachycardia leading to cardiac arrest at 3 months of age. Height and BMI were normal. Blood tests showed elevated CK, a mild increase in liver enzymes and triglycerides levels, and undetectable leptin and adiponectin concentrations. Fasting glucose and HbA1c were normal, while Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was mildly elevated. Both patients were hyperphagic and had cravings for foods rich in fats and sugars. Genetic testing revealed a novel pathogenic mutation of the CAVIN1/PTRF gene (NM_012232 exon1:c T21A:p.Y7X) at the homozygous state. The diagnosis of lipodystrophy can be challenging, often requiring a multidisciplinary approach, given the pleiotropic effect, involving several tissues. The coexistence of generalized lack of fat, myopathy with elevated CK levels, arrhythmias, gastrointestinal dysmotility, and skeletal abnormalities should prompt the suspicion for the diagnosis of CGL4, although phenotypic variability may occur.

Cytological and Ultrasound Features of Thyroid Nodules Correlate With Histotypes and Variants of Thyroid Carcinoma.

CONTEXT: Prognosis is excellent for papillary thyroid carcinoma (PTC), noninvasive follicular thyroid neoplasia with papillary-like nuclear features (NIFT-P), and follicular thyroid carcinoma (FTC) but is poor for poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC). Among PTCs, the prognosis is more favorable for follicular (FV-PTC) and classic (CV-PTC) than for tall cell (TCV-PTC), and solid (SV-PTC) variants. OBJECTIVE: To associate histotypes and variants of thyroid carcinoma with ultrasound and cytological features. METHODS: Histology of 1018 benign tumors and 514 PTC (249 CV, 167 FV, 49 TC, 34 SV, and 15 other variants), 52 NIFT-P, 50 FTC, 11 PDTC, and 3 ATC was correlated with fine-needle aspiration biopsy categories (Italian classification: TIR1, TIR2, TIR3A, TIR3B, TIR4, and TIR5) and ultrasound features at the Endocrinology Unit, University Hospital of Pisa. In total, 1117 patients with thyroid nodule(s) who underwent thyroidectomy were included. RESULTS: Of PTC, 36.3% had indeterminate cytology (TIR3A or TIR3B), 56.6% were suspicious for malignancy or malignant (TIR4 or TIR5); 84.0% FTC and 69.3% NIFT-P were TIR3A or TIR3B; 72.5% FV-PTC and 73.6% SV-PTC were TIR3A or TIR3B; 79.9% CV-PTC and 95.9% TCV-PTC were TIR4 or TIR5. The association of a hypoechoic pattern, irregular margins, and no microcalcifications was more frequent in TCV-PTC than in CV-PTC (P = .02, positive predictive value = 38.9%; negative predictive value = 85.5%). CONCLUSION: At cytology, most FTC, NIFT-P, FV-PTC, and SV-PTC were indeterminate, most CV-PTC and TCV-PTC were suspicious for malignancy or malignant. Ultrasound can be helpful in ruling out TCV-PTC.

Canagliflozin on top of dual renin-angiotensin system blockade in a woman with partial acquired lipodystrophy, type 2 diabetes and severely proteinuric chronic kidney disease: a case report.

Sodium glucose cotransporter 2 inhibitors have proven strong efficacy in reducing end-stage renal disease in patients with type 2 diabetes. We are presenting here the case of a 40-year-old woman with acquired partial lipodystrophy, type 2 diabetes and essential hypertension complicated by chronic kidney disease and proteinuria in the nephrotic range. She first came to our attention in 2012; estimated glomerular filtration rate (eGFR) was 41.5 ml/min/1.73 m2 and total proteinuria was 375 mg/24h; she was treated with dual renin angiotensin system blocking. Proteinuria significantly increased during the following years, reaching a nephrotic range (>5 g/day). A kidney biopsy revealed a tubule-interstitial involvement compatible with type 2 diabetes. Leptin replacement therapy, started in 2018, improved glycaemic control and lipid profile, also determining a reduction in insulin total daily dose. In 2019, after the publication of the CREDENCE study, canagliflozin was started on top of losartan and ramipril. After an initial, expected eGFR drop, kidney function stabilized, and albuminuria significantly reduced (from 4120 to 984 mg/24h), while serum potassium showed only minimal increase. At last follow-up (2022) total proteinuria was still reducing (510 mg/24h), while kidney function was substantially unchanged (eGFR 40 ml/min/1.73 m2). This case report suggests that, despite not recommended in international guidelines, the use of SGLT2i in combination with dual renin angiotensin system blockade should be considered in specific conditions and under close clinical monitoring.

Eating disorders and emotional dysregulation are associated with insufficient weight loss after bariatric surgery: a 1-year observational follow-up study.

PURPOSE: Subjects with obesity, especially those seeking bariatric surgery, exhibit high rates of mental disorders and marked psychopathological traits. The primary objective of this prospective, non-interventional study was to investigate whether the presence of different psychiatric disorders, attention deficit/hyperactivity disorder (ADHD) symptomatology and emotional dysregulation influenced weight loss at 1-year follow-up after surgery. METHODS: Subjects consecutively referred for pre-surgical evaluation at the Obesity Center of Pisa University Hospital were recruited. Psychiatric diagnoses were made through the Mini-International Neuropsychiatric Interview (MINI) and ADHD symptomatology was assessed with the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS). Emotional dysregulation was investigated through the WRAADDS and self-report questionnaires. After surgery, weight and obesity-related comorbidities were monitored during follow-up. RESULTS: Of the 99 participants recruited, 76 underwent surgery and 65 could be reevaluated 1 year after surgery. Subjects with insufficient weight loss (excess body mass index loss ≤ 53%, n = 15) had more frequent lifetime binge eating disorder (BED) and BED-mood disorders comorbidity than subjects with favorable post-surgical outcome. Additionally, they scored higher on both physician-administered and self-report scales assessing emotional dysregulation, which represents a nuclear symptom of ADHD in adults. At the logistic regression analysis, older age, higher preoperative excess body mass index and greater affective instability were predictors of reduced weight loss at 1-year follow-up. CONCLUSION: Emotional dysregulation seems to be associated with a worse outcome after bariatric surgery. Further studies with larger samples and longer follow-up are needed to confirm the influence of different psychiatric disorders and psychopathological traits on post-surgical outcome. LEVEL OF EVIDENCE: V, prospective descriptive study.

Oxidative and DNA damage in obese patients undergoing bariatric surgery: A one-year follow-up study.

The pathogenesis of obesity and related comorbidities has long been associated with oxidative stress. The excess of adipose tissue contributes to the production of free radicals that sustain both a local and a systemic chronic inflammatory state, whereas its reduction can bring to an improvement in inflammation and oxidative stress. In our work, using the fluorescent lipid probe BODIPY® 581/591 C11 and the γH2AX foci assay, a well-known marker of DNA double strand breaks (DSB), we evaluated the extent of cell membrane oxidation and DNA damage in peripheral blood lymphocytes of normal weight (NW) controls and obese patients sampled before and after bariatric surgery. Compared to NW controls, we observed a marked increase in both the frequencies of oxidized cells or nuclei exhibiting phosphorylation of histone H2AX in preoperatory obese patients. After bariatric surgery, obese patients, resampled over one-year follow-up, improved oxidative damage and reduced the presence of DSB. In conclusion, the present study highlights the importance for obese patients undergoing bariatric surgery to also monitor these molecular markers during their postoperative follow-up.

Obesity, Hyperfiltration, and Early Kidney Damage: A New Formula for the Estimation of Creatinine Clearance.

CONTEXT: Glomerular hyperfiltration may represent a direct pathogenetic link between obesity and kidney disease. The most widely used methods to estimate creatine clearance such as Cockroft-Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) have not been validated in subjects with obesity. OBJECTIVE: The performance of prediction formulas was compared with measured creatinine clearance (mCrCl) in subjects with obesity. METHODS: The study population included 342 patients with obesity (mean BMI 47.6 kg/m2) without primary kidney disease. A urine collection was performed over 24 hours for measurement of CrCl. RESULTS: mCrCl increased with body weight. The CG formula showed an overestimation at high CrCl, whereas an underestimation resulted from CKD-EPI and MDRD. To improve the accuracy of estimated CrCl (eCrCl), a new CG-based formula was developed:53+0.7×(140-Age)×Weight/(96xSCr)×(0.85iffemale)A cut-off point for BMI of 32 kg/m2 was identified, at which the new formula may be applied to improve eCrCl. CONCLUSION: In patients with obesity the glomerular filtration rate increases with body weight, and it is associated with the presence of albuminuria, suggesting an early kidney injury. We propose a novel formula that improves the accuracy of eCrCl to avoid missed diagnoses of hyperfiltration in patients with obesity.

Transcriptional changes in multiple endocrine organs from lethal cases of COVID-19.

Altered circulating hormone and metabolite levels have been reported during and post-COVID-19. Yet, studies of gene expression at the tissue level capable of identifying the causes of endocrine dysfunctions are lacking. Transcript levels of endocrine-specific genes were analyzed in five endocrine organs of lethal COVID-19 cases. Overall, 116 autoptic specimens from 77 individuals (50 COVID-19 cases and 27 uninfected controls) were included. Samples were tested for the SARS-CoV-2 genome. The adrenals, pancreas, ovary, thyroid, and white adipose tissue (WAT) were investigated. Transcript levels of 42 endocrine-specific and 3 interferon-stimulated genes (ISGs) were measured and compared between COVID-19 cases (virus-positive and virus-negative in each tissue) and uninfected controls. ISG transcript levels were enhanced in SARS-CoV-2-positive tissues. Endocrine-specific genes (e.g., HSD3B2, INS, IAPP, TSHR, FOXE1, LEP, and CRYGD) were deregulated in COVID-19 cases in an organ-specific manner. Transcription of organ-specific genes was suppressed in virus-positive specimens of the ovary, pancreas, and thyroid but enhanced in the adrenals. In WAT of COVID-19 cases, transcription of ISGs and leptin was enhanced independently of virus detection in tissue. Though vaccination and prior infection have a protective role against acute and long-term effects of COVID-19, clinicians must be aware that endocrine manifestations can derive from virus-induced and/or stress-induced transcriptional changes of individual endocrine genes. KEY MESSAGES: • SARS-CoV-2 can infect adipose tissue, adrenals, ovary, pancreas and thyroid. • Infection of endocrine organs induces interferon response. • Interferon response is observed in adipose tissue independently of virus presence. • Endocrine-specific genes are deregulated in an organ-specific manner in COVID-19. • Transcription of crucial genes such as INS, TSHR and LEP is altered in COVID-19.

Enlargement of a metastatic lymph node from differentiated thyroid cancer after COVID-19 vaccination.

BACKGROUND: The massive vaccination campaign against COVID-19 has granted a high level of protection against the severe forms of the disease at the price of some mild adverse events. OBJECTIVE: To underline that COVID-19 vaccination can induce a transient enlargement of lymph-node metastases in differentiated thyroid cancer patients. CASE PRESENTATION: We describe the clinical, laboratory, and imaging features of a 60-year-old woman affected by paratracheal lymph-node relapse of Hurtle Cell Carcinoma who came to our attention after full COVID-19 vaccination because of neck swelling and pain. In April 2021, after 5 years of stable structural disease, the patient presented an enlargement of the metastatic lymph node, associated with a rise of serum thyroglobulin (from 4.6 to 14.7 pg/mL). Anti-inflammatory treatment was started and pain and swelling remitted after 15 days. At the subsequent evaluation, at neck ultrasound, the right paratracheal lesion was smaller and thyroglobulin dropped to 3.9 pg/mL. CONCLUSIONS: We report the case of an enlargement of metastatic lymph node from differentiated thyroid cancer after COVID-19 vaccination. We warn clinicians to identify features of inflammatory response due to COVID-19 vaccination in order to prevent unwarranted surgical treatment.

Thyroid autoimmunity, thyroglobulin autoantibodies, and thyroid cancer prognosis.

The relevance of thyroid autoimmunity to the prognosis of papillary thyroid carcinoma is still unsettled. We decided to investigate the impact of thyroid autoimmunity on the prognosis of papillary thyroid carcinoma and the handling of TgAbs. We evaluated the clinical course of a large group of patients according to the presence (PTC-LT) or absence (PTC) of lymphocytic thyroiditis at histology. We studied 194 consecutive patients with a diagnosis of PTC and treated them with total thyroidectomy plus ¹³¹I ablation between 2007 and 2009. Median follow-up (with 25th-75th percentiles) was 84.0 (56.4-118.0) months. The remission criteria were: basal Tg < 0.2 ng/mL (or stimulated Tg: < 1), TgAbs < 8 IU/mL (otherwise 'decreasing TgAb trend', a decline of ≥20% in sequential TgAb measurements) and unremarkable imaging. PTC-LT and PTC patients had comparable treatment.TgAbs were detectable in 72.5% of PTC-LT and 16.5% of PTC patients. Time to remission was longer in the detectable than in the undetectable TgAb cohort (28.5 vs· 7.5 months (median); HR: 0.54, CI: 0.35-0.83, P = 0.005). When comparing PTC-LT to PTC patients, the difference was maintained in the detectable TgAb (29.3 vs 13.0 months; HR: 0.38, CI: 0.18-0.80; P = 0.01) but not in the undetectable TgAb cohort (7.7 vs 7.3 months; HR: 0.90, CI: 0.55-1.47; P = 0.68). Using the decreasing TgAb trend, the influence of detectable TgAbs on time to remission was abolished. Thyroid autoimmunity does not influence the prognosis of papillary thyroid carcinoma. A decreasing TgAb trend seems an appropriate criterion to establish the remission of papillary thyroid carcinoma.

Outcomes of the Tall-Cell Variant of Papillary Thyroid Carcinoma in Patients with Different Ages: A 17-Year Mono-Institutional Experience.

The tall-cell variant of papillary thyroid carcinoma (TCPTC) is the most common aggressive variant of papillary thyroid carcinoma (PTC) and typically occurs in older patients. In this study, we analyzed retrospectively the largest mono-institutional series of PTCs with tall-cell features (989 patients) over a 17-year period, re-evaluating tumors based on age at presentation and outcomes in different age groups. We divided patients into three age groups following different criteria (the criterion from the American Joint Committee on Cancer Tumor Node Metastasis (AJCC TNM) guidelines, criterion for the statistical division into tertiles and adolescent/post-adolescent criterion) to analyze the clinicopathological characteristics in different age groups, especially in terms of recurrence-free survival (RFS) and distant recurrence-free survival (DRFS). We obtained three main results: 1. the population is distributed among the different age groups, and therefore, this type of cancer is not exclusively found among those of an older age; 2. in the RFS analysis, we can see a higher probability of local recurrence in the younger and older groups and, unexpectedly, a lower probability of local recurrence in the "median age" group; and 3. in the DRFS analysis, we can observe a higher probability of distant recurrence in older patients. From a molecular perspective, no significant differences in the mutational status of BRAF were detected according to different age groups, while mutations in the TERT promoter were exclusively present in older patients of all age groups, highlighting the potential prognostic implications of TERT promoter mutations in PTCs. In conclusion, the results of this series confirm that TC morphology alone in PTCs does not have the same negative prognostic significance in the younger population as in the older population. The reason for these different outcomes remains unclear and needs further studies.

Sarcopenic obesity research perspectives outlined by the sarcopenic obesity global leadership initiative (SOGLI) - Proceedings from the SOGLI consortium meeting in rome November 2022.

The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) launched the Sarcopenic Obesity Global Leadership Initiative (SOGLI) to reach expert consensus on a definition and diagnostic criteria for Sarcopenic Obesity (SO). The present paper describes the proceeding of the Sarcopenic Obesity Global Leadership Initiative (SOGLI) meeting that was held on November 25th and 26th, 2022 in Rome, Italy. This consortium involved the participation of 50 researchers from different geographic regions and countries. The document outlines an agenda advocated by the SOGLI expert panel regarding the pathophysiology, screening, diagnosis, staging and treatment of SO that needs to be prioritized for future research in the field.

The three facets of the SARS-CoV-2 pandemic during the first two waves in the northern, central, and southern Italy.

BACKGROUND: There is a scarcity of information in literature regarding the clinical differences and comorbidities of patients affected by Coronavirus disease 2019 (COVID-19), which could clarify the different prevalence of the outcomes (composite and only death) between several Italian regions. OBJECTIVE: This study aimed to assess the heterogeneity of clinical features of patients with COVID-19 upon hospital admission and disease outcomes in the northern, central, and southern Italian regions. METHODS: An observational cohort multicenter retrospective study including 1210 patients who were admitted for COVID-19 in Infectious diseases, Pulmonology, Endocrinology, Geriatrics and Internal Medicine Units in Italian cities stratified between north (263 patients); center (320 patients); and south (627 patients), during the first and second pandemic waves of SARS-CoV-2 (from February 1, 2020 to January 31, 2021). The data, obtained from clinical charts and collected in a single database, comprehended demographic characteristics, comorbidities, hospital and home pharmacological therapies, oxygen therapy, laboratory values, discharge, death and Intensive care Unit (ICU) transfer. Death or ICU transfer were defined as composite outcomes. RESULTS: Male patients were more frequent in the northern Italian region than in the central and southern regions. Diabetes mellitus, arterial hypertension, chronic pulmonary and chronic kidney diseases were the comorbidities more frequent in the southern region; cancer, heart failure, stroke and atrial fibrillation were more frequent in the central region. The prevalence of the composite outcome was recorded more frequently in the southern region. Multivariable analysis showed a direct association between the combined event and age, ischemic cardiac disease, and chronic kidney disease, in addition to the geographical area. CONCLUSIONS: Statistically significant heterogeneity was observed in patients with COVID-19 characteristics at admission and outcomes from northern to southern Italy. The higher frequency of ICU transfer and death in the southern region may depend on the wider hospital admission of frail patients for the availability of more beds since the burden of COVID-19 on the healthcare system was less intense in southern region. In any case, predictive analysis of clinical outcomes should consider that the geographical differences that may reflect clinical differences in patient characteristics, are also related to access to health-care facilities and care modalities. Overall, the present results caution against generalizability of prognostic scores in COVID-19 patients derived from hospital cohorts in different settings.

COVID-induced thyroid autoimmunity.

Breakdown of self-tolerance to thyroid antigens (thyroperoxidase, thyroglobulin and the thyrotropin-receptor) is the driver of thyroid autoimmunity. It has been suggested that infectious disease might trigger autoimmune thyroid disease (AITD). Involvement of the thyroid has been reported during severe acute respiratory syndrome virus 2 (SARS-CoV-2) infection, in the form of subacute thyroiditis in subjects with mild coronavirus disease 19 disease (COVID-19) and of painless, destructive thyroiditis in hospitalized patients with severe infection. In addition, cases of AITD, both Graves' disease (GD) and Hashimoto's thyroiditis (HT), have been reported in association with (SARS-CoV-2) infection. In this review, we focus on the relationship between SARS-CoV-2 infection and occurrence of AITD. Nine cases of GD strictly related to SARS-CoV-2 infection and only three cases of HT associated to COVID-19 infection have been reported. No study has demonstrated a role of AITD as a risk factor for a poor prognosis of COVID-19 infection.

Characterization and Clinical Association of Autoantibodies Against Perilipin 1 in Patients With Acquired Generalized Lipodystrophy.

Acquired generalized lipodystrophy (AGL) is a rare condition characterized by massive loss of adipose tissue through the body, causing severe metabolic complications. Autoimmune destruction of adipocytes is strongly suspected based on the frequent association of AGL with autoimmune disorders. In 2018, autoantibodies against perilipin 1 (PLIN1) were identified in three patients with autoimmune-associated AGL. However, the pathogenic mechanism and clinical impact of anti-PLIN1 remain unsolved. The prevalence of anti-PLIN1 autoantibodies in an AGL cohort of 40 patients was 50% (20 of 40). Among positive patients, 10 had the autoimmune variety and 10 had panniculitis-associated AGL. The IgG isotype was predominant, although some IgM antibodies were detected. Epitope-mapping studies did not identify a single, major epitope. Instead, autoantibodies typically bound to several different peptides, among which the central (233-405) domain was detected in all antibody-positive patients, for both IgG and IgM autoantibodies. In-depth epitope mapping indicated that anti-PLIN1 autoantibodies predominantly recognize the αß-hydrolase domain containing 5 (ABHD5) binding site (383-405). Autoantibodies dose-dependently blocked the binding of PLIN1 to ABHD5 and caused a dislocation of ABHD5 toward the cytosol, leading to an increase in lipolysis and lipase activities. Finally, anti-PLIN1 titers significantly correlated with the amount of fat loss, metabolic control impairment, and severity of liver injury. Our data strongly support that anti-PLIN1 autoantibodies are a diagnostic biomarker and a cause of lipodystrophy in patients with AGL.

Autopsy Study of Testicles in COVID-19: Upregulation of Immune-Related Genes and Downregulation of Testis-Specific Genes.

CONTEXT: Infection by SARS-CoV-2 may be associated with testicular dysfunction that could affect male fertility. OBJECTIVE: Testicles of fatal COVID-19 cases were investigated to detect virus in tissue and to evaluate histopathological and transcriptomic changes. METHODS: Three groups were compared: (a) uninfected controls (subjects dying of trauma or sudden cardiac death; n = 10); (b) subjects dying of COVID-19 (virus-negative in testes; n = 15); (c) subjects dying of COVID-19 (virus-positive in testes; n = 9). SARS-CoV-2 genome and nucleocapsid antigen were probed using RT-PCR, in situ hybridization, and immunohistochemistry (IHC). Infiltrating leukocytes were typed by IHC. mRNA transcripts of immune-related and testis-specific genes were quantified using the nCounter method. RESULTS: SARS-CoV-2 was detected in testis tissue of 9/24 (37%) COVID-19 cases accompanied by scattered T-cell and macrophage infiltrates. Size of testicles and counts of spermatogenic cells were not significantly different among groups. Analysis of mRNA transcripts showed that in virus-positive testes immune processes were activated (interferon-alpha and -gamma pathways). By contrast, transcription of 12 testis-specific genes was downregulated, independently of virus positivity in tissue. By IHC, expression of the luteinizing hormone/choriogonadotropin receptor was enhanced in virus-positive compared to virus-negative testicles, while expression of receptors for androgens and the follicle-stimulating hormone were not significantly different among groups. CONCLUSION: In lethal COVID-19 cases, infection of testicular cells is not uncommon. Viral infection associates with activation of interferon pathways and downregulation of testis-specific genes involved in spermatogenesis. Due to the exceedingly high numbers of infected people in the pandemic, the impact of virus on fertility should be further investigated.